Preclinical development and clinical safety assessment of a synthetic peptide conjugate enabling endogenous antibody binding to promote innate receptor engagement

Abstract

Peptide-based vaccines can be used to deliver tumor-specific antigens to dendritic cells (DCs), leading to tumor-directed T cell responses. We previously developed a peptide-peptide conjugate technology enabling in vivo cross-linking of pre-existing tetanus toxin-directed antibodies, facilitating antigen delivery to, and activation of DCs. To achieve this, multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically produce target antigens of choice. Herein, we describe the generation of a prostate cancer vaccine candidate (TENDU) based on this technology. It includes long synthetic peptides harboring epitopes (CD4 and CD8) from prostate-specific antigen (PAP) and prostate-specific membrane antigen (PSMA). The preclinical efficacy of TENDU was assessed in experimental systems, and safety was evaluated in a rabbit toxicity study and a human whole blood loop assay. We also report the first clinical safety assessment of TENDU. Experimental studies showed that prostate cancer patients mounted anti-MTTE antibodies in response to tetanus vaccination with recall T cell responses detected in two patients. Transgenic humanized HLA-DR4 mice displayed T cell responses and increased anti-MTTE IgG levels after vaccination with a peptide construct including an HLA-DR4 epitope. The vaccine candidate was found safe, and a positive correlation between T cell responses and anti-MTTE antibodies was noted in the first-in-human for patients with low-to intermediate-risk prostate cancer typically involve radical prostatectomy or radiation therapy, whereas high-risk prostate cancer is usually treated with androgen deprivation therapy (ADT) in combination with radiotherapy; metastatic disease is treated with ADT and chemotherapy.2 However, in the metastatic setting, ADT only provides a transient therapeutic benefit, and the majority of the patients will eventually progress to castration-resistant prostate cancer with limited treatment options.3,4 The development of novel treatment strategies is therefore essential for this group of patients. One promising approach is immunotherapy, including immune checkpoint inhibitors and other strategies to boost the immune system. Prostate cancer antigens are well described in the literature and different vaccination designs have been developed for the treatment of prostate cancer patients, including the cell-based vaccine sipuleucel-T (Provenge), which targets prostatic acid phosphatase (PAP).5-8 As the prostate is a non-essential organ, the target of a prostate cancer vaccine does not need to be tumor-specific, instead it can be directed to the prostate tissue itself. The best known target antigens include the above-mentioned PAP, as well as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA).9